The instant invention provides naphthamidine compounds which inhibit urokinase, methods for making the compounds, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.
Urokinase is a proteolytic enzyme which is highly specific for a single peptide bond in plasminogen. Plasminogen activation (cleavage of this bond by urokinase) results in formation of plasmin, a potent general protease.
Many cell types use urokinase as a key initiator of plasmin-mediated proteolytic degradation or modification of extracellular support structures such as extracellular matrix (ECM) and basement membrane (BM). Cells exist, move, and interact with each other in tissues and organs within the physical framework provided by ECM and BM. Movement of cells within ECM or across BM requires local proteolytic degradation or modification of the structures and allows cells to invade adjacent areas previously unavailable prior to the degradation or modification.
Cellular invasiveness initiated by urokinase is central to a variety of normal and disease-state physiological processes (J. Cell Biol. 1987, 104, 801-804 and Adv. Cancer Res. 1985, 44, 139-266). Such processes include angiogenesis, bone restructuring, embryo implantation in the uterus, infiltration of immune cells into inflammatory sites, ovulation, spermatogenesis, tissue remodeling during wound repair and organ differentiation, fibrosis, tumor invasion, metastatic spread of tumor cells from primary to secondary sites, and tissue destruction in arthritis. Amiloride, for example, a known urokinase inhibitor of only moderate potency, has been reported to inhibit tumor metastasis in vivo (Anticancer Res. 1988, 8, 1373-1376) and angiogenesis in vitro (J. Cell Biol. 1991, 115[3 Pt 2], 402a).
Inhibitors of urokinase, therefore, have mechanism-based anti-angiogenic, anti-arthritic, anti-inflammatory, anti-retinopathic (for angiogenesis-dependent retinopathies), contraceptive and tumoristatic uses.
In its principle embodiment, the instant invention provides a compound of formula (I): 
or a pharmaceutically acceptable salt thereof, wherein
R1 is hydrogen or hydroxy;
R2 is selected from the group consisting of hydrogen, halo, alkyl, alkenyl, alkynyl, alkoxyalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyl, and xe2x80x94NRaRb, wherein Ra and Rb are independently selected from the group consisting of hydrogen, aryl, and heteroaryl; and 
R3 is
wherein R4 and R5 are on adjacent carbon atoms and, taken together with the carbon atoms to which they are attached, are pyridine or a nitrogen-containing heterocycloalkyl,
wherein the groups defining R3 can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy, hydroxyalkyl, aryl, arylalkyl, alkanoyl, alkoxycarbonyl, alkenyl, alkynyl, halo, haloalkyl, heteroaryl, heteroarylalkyl, and a nitrogen protecting group.
In another embodiment, the instant invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
In another embodiment, the instant invention provides a method of inhibiting urokinase in a mammal in recognized need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
In another embodiment, the instant invention provides a method for the preparation of a compound of formula (I), the method comprising:
(a) reacting a compound of formula (Ia): 
xe2x80x83wherein Rf is cyano or xe2x80x94C(xe2x95x90NR1)NH2 and wherein R2 and R3 are as previously defined, with diazomethane or trimethylsilyldiazomethane in the presence of a palladium catalyst;
(b) optionally reacting the product from step (a) with an anionic nitrogen source.
Compounds of the instant invention comprise 6,8-disubstituted 2-naphthamidines which are useful for the treatment of urokinase-mediated diseases.
When used throughout this specification and the appended claims, the following terms have the meanings indicated:
The term xe2x80x9calkanoyl,xe2x80x9d as used herein, represents an alkyl group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, represents a monovalent straight or branched chain group of one to six carbon atoms containing at least one carbon-carbon double bond. The alkenyl groups of this invention can be optionally substituted with an alkoxy, amino, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, thioalkoxy, thioaryloxy, or thioheteroaryloxy substituent, wherein the aryl and the heteroaryl substituents can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, amino, halo, and cycloalkyl.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, represents an alkyl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, represents an alkoxy group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, represents an alkoxy group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9calkyl,xe2x80x9d as used herein, represents a saturated straight or branched chain monovalent group of one to six carbon atoms derived from a hydrocarbon group. The alkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, represents a monovalent straight or branched chain group of one to six carbon atoms containing at least one carbon-carbon triple bond. The alkynyl groups of this invention can be optionally substituted with an alkoxy, amino, aryl, aryloxy, heteroaryl, heteroaryloxy, hydroxy, thioalkoxy, thioaryloxy, or thioheteroaryloxy substituent, wherein the aryl and the heteroaryl substituents can be further optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkoxy, amino, halo, and cycloalkyl.
The term xe2x80x9camino,xe2x80x9d as used herein, represents xe2x80x94NR10R11, wherein R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, arylalkyl, cycloalkyl, and (cycloalkyl)alkyl; or R10 and R11, together with the nitrogen atom to which they are attached, form a ring selected from the group consisting of piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl dioxide, piperidinyl, and pyrrolidinyl.
The term xe2x80x9canionic nitrogen source,xe2x80x9d as used herein, represents lithium hexamethyldisilazide, potassium hexamethyldisilazide, or sodium hexamethyldisilazide.
The term xe2x80x9caryl,xe2x80x9d as used herein, represents phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, and indenyl. Aryl groups having an unsaturated or partially saturated ring fused to an aromatic ring such as dihydronaphthyl, tetrahydronaphthyl, and indanyl can be attached through either the saturated or unsaturated part of the group. The aryl groups of this invention can be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkanoyl, alkyl, alkoxy, alkoxyalkyl, cycloalkyl, (cycloalkyl)alkyl, perfluoroalkyl, hydroxy, hydroxyalkyl, halo, haloalkyl, nitro, alkoxycarbonyl, perfluoroalkoxy, and xe2x80x94NRcRd, wherein Rc and Rd are independently hydrogen or alkyl.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, represents a saturated monovalent cyclic hydrocarbon.
The term xe2x80x9c(cycloalkyl)alkyl,xe2x80x9d as used herein, represents a cycloalkyl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9chalo,xe2x80x9d as used herein, represents F, Cl, Br, and I.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, represents an alkyl group substituted by one, two, three, or four halogen atoms.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, represents a cyclic, aromatic group having five or six ring atoms, wherein at least one ring atom is selected from the group consisting of oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon. The five-membered rings have two double bonds and the six-membered rings have three double bonds. Heteroaryl groups of this invention include those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, thiene, triazole, and tetrazole by the removal of a hydrogen atom from a carbon atom in the ring. The term xe2x80x9cheteroarylxe2x80x9d also includes bicyclic groups in which any of the above heteroaryl rings is fused to a phenyl ring. Examples of bicyclic heteroaryls include benzofuryl, benzothienyl, indolyl, isoquinolinyl, and quinolinyl, and the like. The heteroaryl groups of this invention can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy, hydroxyalkyl, aryl, arylalkyl, alkanoyl, alkoxycarbonyl, alkenyl, alkynyl, halo, haloalkyl, heteroaryl, heteroarylalkyl, a nitrogen protecting group, and xe2x80x94NRcRd, wherein Rc and Rd are as previously defined.
The term xe2x80x9cheteroarylalkyl,xe2x80x9d as used herein, represents a heteroaryl group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9cheteroaryloxy,xe2x80x9d as used herein, represents a heteroaryl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9cheterocycloalkyl,xe2x80x9d as used herein, represents a non-aromatic five-, six- or seven-membered ring having between one and three heteroatoms independently selected from oxygen, sulfur, and nitrogen. The five-membered rings have zero to one double bond, the six-membered ring has zero to two double bonds, and the seven-membered ring has zero to three double bonds. Heterocycloalkyl groups of this invention include those derived from 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 3,4-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, and piperidinyl by the removal of a hydrogen atom from a carbon atom in the ring. Heterocycloalkyl groups can also be fused to phenyl rings to provide bicyclic groups which can be attached to the parent molecular moiety through a carbon atom on either the phenyl part or the heterocycloalkyl part of the bicyclic group. Examples of these fused heterocycloalkyls include 1,2,3,4-tetrahydro-5-isoquinolinyl, 1,2,3,4-tetrahydro-6-isoquinolinyl, 1,2,3,4-tetrahydro-7-isoquinolinyl, 1,2,3,4-tetrahydro-8-isoquinolinyl, 3,4-dihydro-5-isoquinolinyl, 3,4-dihydro-6-isoquinolinyl, 3,4-dihydro-7-isoquinolinyl, 3,4-dihydro-8-isoquinolinyl, and the like. The heterocycloalkyl groups of this invention can be optionally substituted with one, two, three, or four substituents independently selected from the group consisting of alkyl, cycloalkyl, (cycloalkyl)alkyl, hydroxy, hydroxyalkyl, aryl, arylalkyl, alkanoyl, alkoxycarbonyl, alkenyl, alkynyl, halo, haloalkyl, heteroaryl, heteroarylalkyl, a nitrogen protecting group, and xe2x80x94NRcRd, wherein Rc and Rd are as previously defined.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, represents xe2x80x94OH.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, represents a hydroxy group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9cnitro,xe2x80x9d as used herein, represents xe2x80x94NO2.
The term xe2x80x9cnitrogen-protecting group,xe2x80x9d as used herein, represents groups intended to protect an amino group against undesirable reactions during synthetic procedures. Common nitrogen-protecting groups comprise formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, orthonitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl, benzenesulfonyl, and para-toluenesulfonyl, benzyloxycarbonyl, para-chlorobenzyloxycarbonyl, para-methoxybenzyloxycarbonyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and the like.
The term xe2x80x9cpalladium catalyst,xe2x80x9d as used herein, refers to palladium complexes which enhance the rate of reactions. Examples of catalysts include palladium (II) acetate, palladium (II) chloride, and palladium (II) dibenzylideneacetone. Each of these catalysts can be used with triphenylphosphine, triphenylarsine, or a trialkylphosphine such as tributylphosphine optionally present.
The term xe2x80x9cperfluoralkoxy,xe2x80x9d as used herein, represents a perfluoroalkyl group attached to the parent molecular moiety through an oxygen atom.
The term xe2x80x9cperfluoroalkyl,xe2x80x9d as used herein, represents an alkyl group wherein each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical.
The term xe2x80x9cpharmaceutically acceptable salt,xe2x80x9d as use herein, represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the instant invention or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, trifluoroacetate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
The term xe2x80x9cprodrug,xe2x80x9d as used herein, represents compounds that are rapidly transformed in vivo to yield the parent compounds of formula (I), such as, for example, by hydrolysis in blood. Prodrugs of these compounds include compounds of formula (I), wherein R1 is hydroxy.
The term xe2x80x9cthioalkoxy,xe2x80x9d as used herein, represents an alkyl group attached to the parent molecular moiety through a sulfur atom.
The term xe2x80x9cthioaryloxy,xe2x80x9d as used herein, represents an aryl group attached to the parent molecular moiety through a sulfur atom.
The term xe2x80x9cthioheteroaryloxy,xe2x80x9d as used herein, represents a heteroaryl group attached to the parent molecular moiety through a sulfur atom.
In accordance with methods of treatment and pharmaceutical compositions of the instant invention, the compounds can be administered alone or in combination with other inhibiting agents. When using the compounds, the specific therapeutically effective dose level for any particular patient will depend upon factors such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the compound employed; the duration of treatment; and drugs used in combination with or coincidently with the compound used. The compounds can be administered orally, parenterally, osmotically (nasal sprays), rectally, vaginally, or topically in unit dosage formulations containing carriers, adjuvants, diluents, vehicles, or combinations thereof. The term xe2x80x9cparenteralxe2x80x9d includes infusion as well as subcutaneous, intravenous, intramuscular, and intrasternal injection.
Parenterally adminstered aqueous or oleaginous suspensions of the compounds can be formulated with dispersing, wetting, or suspending agents. The injectable preparation can also be an injectable solution or suspension in a diluent or solvent. Among the acceptable diluents or solvents employed are water, saline, Ringer""s solution, buffers, monoglycerides, diglycerides, fatty acids such as oleic acid, and fixed oils such as monoglycerides or diglycerides.
The inhibitory effect of parenterally administered compounds can be prolonged by slowing their absorption. One way to slow the absorption of a particular compound is administering injectable depot forms comprising suspensions of crystalline, amorphous, or otherwise water-insoluble forms of the compound. The rate of absorption of the compound is dependent on its rate of dissolution which is, in turn, dependent on its physical state. Another way to slow absorption of a particular compound is administering injectable depot forms comprising the compound as an oleaginous solution or suspension. Yet another way to slow absorption of a particular compound is administering injectable depot forms comprising microcapsule matrices of the compound trapped within liposomes, microemulsions, or biodegradable polymers such as polylactide-polyglycolide, polyorthoesters or polyanhydrides. Depending on the ratio of drug to polymer and the composition of the polymer, the rate of drug release can be controlled.
Transdermal patches can also provide controlled delivery of the compounds. The rate of absorption can be slowed by using rate controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound can optionally comprise diluents such as sucrose, lactose, starch, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, tableting lubricants, and tableting aids such as magnesium stearate or microcrystalline cellulose. Capsules, tablets and pills can also comprise buffering agents, and tablets and pills can be prepared with enteric coatings or other release-controlling coatings. Powders and sprays can also contain excipients such as talc, silicic acid, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons or substitutes therefor.
Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs comprising inert diluents such as water. These compositions can also comprise adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
Topical dosage forms include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and transdermal patches. The compound is mixed under sterile conditions with a carrier and any needed preservatives or buffers. These dosage forms can also include excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Suppositories for rectal or vaginal administration can be prepared by mixing the compounds with a suitable nonirritating excipient such as cocoa butter or polyethylene glycol, each of which is solid at ordinary temperature but fluid in the rectum or vagina. Ophthalmic formulations comprising eye drops, eye ointments, powders, and solutions are also contemplated as being within the scope of the instant invention.
The total daily dose of the compounds administered to a host in single or divided doses can be in amounts from about 0.1 to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight. Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose.
Preferred embodiments of the instant invention include, but are not limited to, compounds of formula (I) and formula (Ia), wherein R3 is optionally substituted isoquinolinyl, optionally substituted 3,4-dihydro-6-isoquinolinyl, optionally substituted 3,4-dihydro-7-isoquinolinyl, optionally substituted 1,2,3,4-tetrahydro-6-isoquinolinyl, optionally substituted 1,2,3,4-tetrahydro-7-isoquinolinyl, or optionally substituted 3,4-dihydro-6-isoquinolinyl.
Specific compounds of the instant invention include, but are not limited to,
8-(3-furyl)-6-(2-(1-isopropyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
8-(3-furyl)-6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-8-((1E)-3-methoxy-1-propenyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl-8-((1E)-3-methoxy-1-propenyl)-2-naphthalenecarboximidamide,
Nxe2x80x2-hydroxy-6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-8-((1E)-3-methyl-1-butenyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-8-tetrahydro-3-furanyl-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-8-((1E)-3-methyl-1-butenyl)-2-naphthalenecarboximidamide,
6-(2-(1-cyclohexyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-phenyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(2-methyl-1-propyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-cyclohexyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(2-acetyl-1-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(2-benzyl-1-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-2-(3-pyridinylmethyl)-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl-2-naphthalenecarboximidamide,
6-(2-(2-cyclopropylmethyl)-1-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(2-ethyl-1-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(2-allyl-1-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1,2-diisopropyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-((1S,2S)-2-(1-isopropyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
xe2x80x94((1R,2R)-2-(1-isopropyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(4,4-diethyl-1-isopropyl-3,4-dihydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(4,4-diethyl-1-isopropyl-3,4-dihydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(4,4-diethyl-1-isopropyl-2-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-2-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
8-((1E)-3,3-dimethyl-1-butenyl)-6-(2-(1-isopropyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
8-bromo-6-(2-(1-isopropyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
8-bromo-6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-8-((1E)-3-methyl-1-butenyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-8-((1E)-3-methyl-1,3-butanienyl)-2-naphthalenecarboximidamide,
8-cyclopropyl-6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-8-(2-methoxyphenyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-8-vinyl-2-naphthalenecarboximidamide,
6-(2-(1,2,3,4-tetrahydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(2-acetyl-1,2,3,4-tetrahydro-6-isoquinolinyl)cyclopropyl)-Nxe2x80x2-hydroxy-2-naphthalenecarboximidamide,
6-(2-(4-ethyl-1,2,3,4-tetrahydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-((2-(2-benzyl-4-ethyl-1,2,3,4-tetrahydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(4-ethyl-2-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-3,4-dihydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-isopropyl-3,4-dihydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(4-ethyl-1-isopropyl-3,4-dihydro-6-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
8-bromo-6-(2-(1-cyclohexyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
8-bromo-6-(2-(1-cyclohexyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide,
6-(2-(1-cyclohexyl-3,4-dihydro-7-isoquinolinyl)cyclopropyl)-8-((1E)-3-methyl-1-butenyl)-2-naphthalenecarboximidamide,
6-(2-(1-cyclohexyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-8-((1E)-3-methyl-1-butenyl)-2-naphthalenecarboximidamide, and
8-allyl-6-(2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)cyclopropyl)-2-naphthalenecarboximidamide.
Determination of Biological Activity
The efficacy of the compounds of the instant invention as urokinase inhibitors was determined by measuring the inhibition of the urokinase enzyme Abbokinase (Abbott Laboratories, Abbot Park, Ill.) on substrate S-2444 of formula pyroGlu-Arg-pNA-HCl (DiaPharma Group, Inc. Distributor of Chromogenix) at 200 xcexcM.
The assay was preformed in a 96 well polystyrene, flat bottom plate in a 50 mM Tris/0.15 M NaCl+0.5% Pluronic F-68 (Sigma P-5556), pH 7.4 with HCl buffer. The compounds of this invention, 10 mM in DMSO, were diluted with DMSO to eight half log concentrations, for example: 1200 xcexcM, 400 xcexcM, 120 FM, 40 xcexcM, 12 xcexcM, 4 xcexcM and 0.4 xcexcM. Four concentrations were chosen, then 5 xcexcl of each were diluted to a total assay volume of 200 xcexcL. The final compound concentrations in the asssay, according to the above example, were 30 xcexcM, 10 xcexcM, 3 xcexcM, 1 xcexcM, 0.3 xcexcM. 0.03 xcexcM and 0.01 xcexcM, respectively. The substrate S-2444 was used at 200 xcexcM in the assay. Several vials were reconstituted as directed on the vile, aliquoted, and stored frozen. The enzyme was further diluted in assay buffer and 10 xcexcL was used in the assay. Enzyme concentration in the assay was 2-3 nM. The assay was performed as follows: 175 xcexcL of buffer was pipetted into the polystyrene plate, and 5 xcexcL solution of a compound of this invention in DMSO was added. The mixture was vortexed, treated with 10 xcexcL of enzyme in buffer, vortexed, treated with 10 xcexcL of substrate in water, and vortexed. The plate was placed in a Spectromax(copyright) (Molecular Devices Corporation, Sunnyvale, Calif.) plate reader to follow the course of the reaction for 15 minutes at 405 nm. The Spectromax(copyright) calculated the reaction rates which were used to calculate percent inhibition of the compounds of this invention versus the reaction rate of the enzyme in the absence of any inhibitor. The Ki""s of the inhibitors were calculated from the percent inhibition and previously established Km. The compounds of this invention inhibit urokinase as shown by the data for representative examples in Table 1.
The pharmacokinetic behavior of selected compounds of formula (I) were evaluated in Sprague-Dawley rats and cynomolgus monkeys. In a series of parallel studies, groups of male rats (n=3/group) and female cynomolgus monkeys (n=3/group) received a single 5 mg/kg IV or oral dose of selected compounds of formula (I). The compounds were prepared as solutions in either 0.2% hydroxpropyl methyl cellulose in water containing approximately 5% DMSO or in an ethanol:propylene glycol:D5W vehicle containing sodium hydroxide or hydrochloric acid (as needed for solubility) for both oral and IV dosing. All animals were fasted overnight prior to dosing and throughout the study. Water was provided freely. Sequential blood samples were obtained from each animal at selected time points after dosing. Plasma was separated by centrifugation at 4xc2x0 C. and frozen until analysis. The parent drug was selectively removed from the plasma contaminants by liquid-liquid extraction with a mixture of ethyl acetate and hexanes under acidic conditions. The parent drug was separated from coextracted contaminants using reverse phase HPLC with MS quantitation of the analytes. The plasma concentrations of the representative compounds of formula (I) were plotted as plasma concentrations (xcexcg/mL) versus time (hours after dosing) for both the IV and oral dosing, and areas under the curve (AUC""s) were determined for each method of dosing. The data were normalized, and the fraction of drug available systemically (F) was determined for the representative compounds of formula (I) by dividing the AUC for the oral dosing by the AUC for the IV dosing. The representative compounds of formula (I) tested showed surprisingly high F values, indicating excellent systemic blood levels.
As shown by the good oral bioavailability and the high F value determined from the pharmacokinetic studies, the compounds of the instant invention, including, but not limited to, those specified in the examples, are useful for the treatment of disease caused or exascerbated by urokinase.
Synthetic Methods
Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: THF for tetrahydrofuran; MTBE for methyl tert-butyl ether; LAH for lithium aluminum hydride; DMAP for 4-dimethylaminopyridine; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; NBS for N-bromosuccinimide; DMF for N,N-dimethylformamide; NMP for N-methylpyrrolidinone; DME for 1,2-dimethoxyethane; LiHMDS for lithium hexamethyldisilazide; LDA for lithium diisopropylamine; KHMDS for potassium hexamethyldisilazide; NaHMDS for sodium hexamethyldisilazide, OAc for acetate; dba for dibenzylideneacetone; TFA for trifluoroacetic acid; and BF3.OEt2 for boron trifluoride etherate.
The compounds and processes of the instant invention will be better understood in connection with the following synthetic schemes which illustrate methods by which the compounds of the instant invention can be prepared. The compounds can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-7. The groups R1, R2, R3, R4, and R5 are defined above. It will be readily apparent to one of ordinary skill in the art that the compounds can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below. 
As shown in Scheme 1, compounds of formula (1) can be condensed with compounds of formula (2) (X is OAc or Cl) in the presence of base to provide compounds of formula (3). Representative bases include triethylamine, DMAP, pyridine, and 2,6-lutidine. Examples of solvents used in these reactions include dichloromethane, 1,2-dichloroethane, carbon tetrachloride, chloroform. The reaction temperature is about 10xc2x0 C. to about 40xc2x0 C. and depends on the method chosen. Reaction times are typically about 1 to about 12 hours. In a preferred embodiment, compounds of formula (1) in dichloromethane at room temperature are treated with compounds of formula (2), triethylamine, and DMAP, and stirred for 3 hours to provide compounds of formula (3).
Compounds of formula (3) can be converted to compounds of formula (4) by treatment with oxalyl chloride in the presence of ferrous (III) chloride, and treatment of the resulting product with sulfuric acid. Examples of solvents used in these reactions include dichloromethane, 1,2-dichloroethane, carbon tetrachloride, and chloroform. Reaction temperatures are about xe2x88x9278xc2x0 C. to about 70xc2x0 C., and reaction times are typically about 1 to about 48 hours.
Conversion of compounds of formula (4) to compounds of formula (5) can be accomplished by treatment with a formylating agent. Representative formylating agents include CO/catalytic palladium, butyllithium/N,N-dimethylformamide, butyllithium/N-formylmorpholine, and butyllithium/N-formylpiperidine. Examples of solvents used in these reactions include TEL, dioxane, diethyl ether, and MTBE. The reaction temperature is about xe2x88x9278xc2x0 C. to about 50xc2x0 C. and depends on the method chosen. Reaction times are about 0.5 to about 12 hours. In a preferred embodiment, compounds of formula (3) in THE at xe2x88x9278xc2x0 C. are treated with butyllithium and N-formylmorpholine, warmed to room temperature, and stirred for 15 minutes to provide compounds of formula (5). 
As shown in Scheme 2, compounds of formula (6) can be converted to compounds of formula (7) by treatment with trifluormethanesulfonic anhydride in the presence of base. Representative bases include triethylamine, diisopropylethylamine, pyridine, and 2,6-lutidine. Examples of solvents used in these reactions include dichloromethane, 1,2-dichloroethane, carbon tetrachloride, and chloroform. The reaction temperature is about xe2x88x9210xc2x0 C. to about 35xc2x0 C. and depends on the method chosen. Reaction times are typically about 2 to about 48 hours. In a preferred embodiment, compounds of formula (6) in dichloromethane at 0xc2x0 C. are treated with trifluoromethanesulfonic anhydride in the presence of triethylamine, warmed to room temperature, and stirred for 48 hours to provide compounds of formula (7).
Conversion of compounds of formula (7) to compounds of formula (8) can be accomplished by treatment with carbon monoxide in the presence of catalytic palladium, water, and base, followed by treatment with N,O-dimethylhydroxylamine hydrochloride in the presence of an activating agent and base. Representative palladium catalysts include PdCl2(dppf), PdCl2(PPh3)2, and Pd(OAc)2, and representative bases include triethylamine, diisopropylethylamine, pyridine, and 2,6-lutidine. Examples of activating agents used in these reactions include (O-(-7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate, O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate, and O-benzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate. Representative solvents include THF, MTBE, diethyl ether, and 1,2-dimethoxyethane. The reaction temperature is about 20xc2x0 C. to about 125xc2x0 C. and depends on the method chosen. Reaction times are typically about 12 to about 48 hours. In a preferred embodiment, compounds of formula (7) in THF and water are treated with triethylamine and PdCl2(dppf), heated to 115xc2x0 C., stirred under 400 psi of carbon monoxide for 18 hours, cooled to room temperature, filtered, treated with diisopropylethylamine, N,O-dimethylhydroxylamine hydrochloride, and (O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophoshphate, and stirred for 16 hours to provide compounds of formula (8).
Compounds of formula (8) can be converted to compounds of formula (9) by treatment with a reducing agent. Representative reducing agents include LAH, sodium triacetoxyborohydride, lithium tri-tert-butoxyaluminohydride, and diisobutylaluminum hydride. Examples of solvents used in these reactions include THF, 1,2-dimethoxyethane, MTBE, and diethyl ether. The reaction temperature is about xe2x88x9210xc2x0 C. to about 25xc2x0 C. and depends on the method chosen. Reaction times are typically about 0.5 to about 12 hours. In a preferred embodiment, compounds of formula (8) in THF at 0xc2x0 C. are treated with LAH and stirred for 30 minutes to provide compounds of formula (9). 
As shown in Scheme 3, compounds of formula (10) can be converted to compounds of formula (11) by treatment with base. Representative bases include potassium hydroxide, lithium hydroxide, and sodium hydroxide. Examples of solvents used in these reactions include methanol, ethanol, water, dioxane, and mixtures thereof. The reaction temperature is about 25xc2x0 C. to about 110xc2x0 C. and depends on the method chosen. Reaction times are typically about 0.5 to about 12 hours. In a preferred embodiment, compounds of formula (10) in dioxane are treated with potassium hydroxide in methanol, heated to 70xc2x0 C., and stirred for 30 minutes to provide compounds of formula (11).
Conversion of compounds of formula (11) to compounds of formula (12) can be accomplished by treatment with a chlorinating agent in the presence of catalytic base. Representative chlorinating agents include SOCl2, PCl5, and PPh3/CCl4. Examples of bases used in these reactions include DMAP, DBU, and 2,6-lutidine. Representative solvents include toluene, hexanes, benzene, and mesitylene. The reaction temperature is about 25 to about 100xc2x0 C. and depends on the method chosen. Reaction times are typically about 0.5 to about 12 hours. In a preferred embodiment, compounds of formula (11) in toluene are treated with thionyl chloride and DMAP, heated to reflux for 1 hour, cooled to 85xc2x0 C., and stirred for 0.5 hours to provide compounds of formula (12).
Compounds of formula (12) can be converted to compounds of formula (13) by treatment with ammonia. Examples of solvents used in this reaction include dichloromethane, carbon tetrachloride, 1,2-dichloroethane, and chloroform. The reaction temperature is about 20xc2x0 C. to about 45xc2x0 C. and depends on the method chosen. Reaction times are typically about 10 minutes to about 1 hour. In a preferred embodiment, compounds of formula (12) in dichloromethane at room temperature are treated with dry ammonia gas for 15 minutes to provide compounds of formula (13).
Conversion of compounds of formula (13) to compounds of formula (14) can be accomplished by treatment with a dehydrating reagent. Representative dehydrating reagents include triphosgene, phosgene, SOCl2, and P2O5. Examples of solvents used in these reactions include, trimethylphosphite, DMF, pyridine, and mixtures thereof. The reaction temperature is about 25xc2x0 C. to about 100xc2x0 C. and depends on the method chosen. Reaction times are typically about 0.5 to about 12 hours. In a preferred embodiment, compounds of formula (13) in trimethylphosphite at room temperature are treated with triphosgene, stirred for 20 minutes, heated to 80xc2x0 C., and stirred for 1 hour to provide compounds of formula (14).
Compounds of formula (14) can be converted to compounds of formula (15) by treatment with a brominating agent. Representative brominating agents include NBS, dibromodimethylhydantoin/trifluoromethanesulfonic acid, Br2, and HOBr. Examples of solvents used in these reactions include dichloromethane, carbon tetrachloride, chloroform, and 1,2-dichloroethane. The reaction temperature is about 25xc2x0 C. to about 50xc2x0 C. and depends on the method chosen. Reaction times are typically about 1 to about 36 hours. In a preferred embodiment, compounds of formula (14) in dichloromethane at room temperature are treated with dibromodimethylhydantoin and trifluoromethanesulfonic acid and stirred for 18 hours to provide compounds of formula (15). 
As shown in Scheme 4, compounds of formula (15) can be converted to compounds of formula (16) by treatment with a reducing agent. Representative reducing agents include borane/pyrrolidine complex, LAH, diisobutylalumnium hydride, CaBH4, and lithium tri-tert-butoxyaluminum hydride. Examples of solvents used in these reactions include THF, pentane, MTBE, diethyl ether, and mixtures thereof. The reaction temperature is about xe2x88x9210xc2x0 C. to about 30xc2x0 C. and depends on the method chosen. Reaction times are typically about 0.5 to about 12 hours. In a preferred embodiment, compounds of formula (15) at 0xc2x0 C. are treated with a solution of borane/pyrrolidine in THF and pentane, stirred for 15 minutes, warmed to room temperature, and stirred for 5 hours to provide compounds of formula (16).
Conversion of compounds of formula (16) to compounds of formula (17) can be accomplished by treatment with a brominating agent. Representative brominating agents include NBS/PPh3,LiBr/PBr3, Br2/PPh3, and CBr4/PPh3. Examples of solvents used in these reactions include dichloromethane, 1,2-dichloroethane, and THF. The reaction temperature is about 0xc2x0 C. to about 35xc2x0 C. and depends on the method chosen. Reaction times are typically about 8 to about 24 hours. In a preferred embodiment, compounds of formula (16) are treated with PPh3 and NBS, warmed to room temperature, and stirred for 16 hours to provide compounds of formula (17).
Compounds of formula (17) can be converted to compounds of formula (18) by treatment with a trialkylphosphite. Representative trialkylphosphites include trimethylphosphite and triethylphosphite. Examples of solvents used in these reactions include DMF, NMP, dioxane, and DME. The reaction temperature is about 80xc2x0 C. to about 160xc2x0 C. and depends on the method chosen. Reaction times are typically about 1 to about 12 hours. In a preferred embodiment, compounds of formula (17) in DMF are treated with triethylphospite, heated to 155xc2x0 C., and stirred for 3 hours to provide compounds of formula (18). 
As shown in Scheme 5, compounds of formula (18) can be condensed with compounds of formula (5) (synthesized in Scheme 1) or with compounds of formula (9) (synthesized in Scheme 2) in the presence of base to provide compounds of formula (19). Representative bases include LiHMDS, LDA, KHMDS, and butyllithium. Examples of solvents used in these reactions include THF, DME, diethyl ether, and MTBE. The reaction temperature is about 0xc2x0 C. to about 25xc2x0 C., and depends on the method chosen. Reaction times are typically about 0.5 to about 12 hours. In a preferred embodiment, compounds of formula (18) in THF at 5xc2x0 C. are treated with LiHMDS, stirred for 30 minutes, treated with compounds of formula (5) or compounds of formula (9), warmed to room temperature, and stirred for 16 hours to provide compounds of formula (19).
Compounds of formula (20) can be prepared by the cross-coupling of compounds of formula (19) with an appropriately substituted organometallic reagent (R2-M) in the presence of a catalyst. Representative coupling partners include organoboranes, organomagenesium halides, and organostannanes. Examples of catalysts used in these reactions include Pd(PPh3)4, PdCl2(PPh3)2, and Pd(OAc)2. Solvents used in these reactions include THF, NMP, DMF, and acetonitrile. The reaction temperature is about 25xc2x0 C. to about 100xc2x0 C. and depends on the method chosen. Reaction times are typically about 1 to about 24 hours.
Compounds of formula (20) can be converted to compounds of formula (21) by treatment with diazomethane or trimethylsilyldiazomethane in the presence of a palladium catalyst. Representative palladium catalysts include Pd(OAc)2, PdCl2, and Pd2(dba)3. Examples of solvents used in these reactions include THF, diethyl ether, and MTBE. The reaction temperature is about xe2x88x9210xc2x0 C. to about 25xc2x0 C. and depends on the method chosen. Reaction times are typically about 30 minutes to about 1 hour. In a preferred embodiment, compounds of formula (20) in THF are treated with diazomethane and Pd(OAc)2 and stirred for 20 minutes to provide compounds of formula (21). 
As shown in Scheme 6, compounds of formula (22) can be converted to compounds of formula (23) by treatment with a reducing agent. Representative reducing agents include diisobutylaluminum hydride, sodium borohydride, and sodium triacetoxyborohydride. Examples of solvents used in these reactions include methanol, ethanol, isopropanol, and n-propanol. The reaction temperature is about 20xc2x0 C. to about 40xc2x0 C. and depends on the method chosen. Reaction times are typically about 0.5 to about 6 hours. In a preferred embodiment, compounds of formula (22) in methanol at room temperature are treated with sodium borohydride and stirred for 30 minutes to provide compounds of formula (23).
Conversion of compounds of formula (23) to compound of formula (24) can be accomplished by treatment with an appropriately substituted aldehyde in the presence of a reducing agent (R9 is alkyl), or by treatment with an acylating agent in the presence of base (R9 is acyl). Representative reducing agents include sodium triacetoxyborohydride and sodium cyanoborohydride, while representative bases include potassium carbonate, sodium carbonate, and sodium bicarbonate. Examples of solvents used in these reactions include dichloromethane, dioxane, chloroform, and THF. The reaction temperature is about xe2x88x9210xc2x0 C. to about 35xc2x0 C. and depends on the method chosen. Reaction times are typically about 2 to about 36 hours.
Compounds of formula (24) can be converted to compounds of formula (25) by treatment with an anionic nitrogen source such as lithium hexamethyldisilazide, potassium hexamethyldisilazide, or sodium hexamethyldisilazide followed by treatement with acid. Representative acids include HCl, H2SO4, and HNO3. Examples of solvents used in this reaction include THF, hexanes, MTBE, diethyl ether, and mixtures thereof. The reaction temperature is about xe2x88x9210xc2x0 C. to about 35xc2x0 C. and depends on the method chosen. Reaction times are typically about 1 to about 36 hours. In a preferred embodiment, compounds of formula (24) in THF at 0xc2x0 C. are treated with lithium hexamethyldisilazide in hexanes, warmed to room temperature, stirred for 18 hours, treated with 10% HCl, and stirred for 24 hours to provide compounds of formula (25).
Compounds of formula (24) can also be converted to compounds of formula (26) by treatment with hydroxylamine. Examples of solvents used in this reaction include ethanol, methanol, and isopropanol. The reaction temperature is about 25xc2x0 C. to about 100xc2x0 C. and depends on the method chosen. Reaction times are typically about 1 to about 12 hours. In a preferred embodiment, compounds of formula (24) in ethanol are treated with hydroxylamine hydrochloride and triethylamine, heated to 80xc2x0 C., and stirred for 2.5 hours to provide compounds of formula (26). 
As shown in Scheme 7, compounds of formula (28) can be subjected to deprotection conditions to provide compounds of formula (29). Representative deprotection conditions include HCl, TFA, trimethylsilyliodide, and aluminum trichloride. Examples of solvents used in these reactions include dichloromethane, chloroform, water, THF, and mixtures thereof. The reaction temperature is about 0xc2x0 C. to about 50xc2x0 C. and depends on the method chosen. Reaction times are typically about 0.5 to about 12 hours. In a preferred embodiment, compounds of formula (28) in dichloromethane at room temperature are treated with trifluoroacetic acid and stirred for 1 hour to provide compounds of formula (29).
Compounds of formula (29) can be converted to compounds of formula (30) and subsequently to compounds of formula (31) or (32) following the procedures described in Scheme 6.